Niacin has been used as first-line drug therapy for elevated serum cholesterol because of its broad efficacy on multiple lipid components as well as its low cost. However, high dose oral formulations of niacin have raised concerns with respect to liver toxicity and unpleasant side effects such as "flushing" that result from the vasodilatory effects of niacin. Consequently, patient compliance with this therapy is problematic. The objective of the research proposed in this application is to determine the feasibility of developing a transdermal delivery form of nicotinic acid for the treatment of hyperlipidemia in order to circumvent the side effects associated with its oral administration. Our preliminary results indicate that tissue saturation by niacin via transdermal delivery is feasible and that transdermal delivery via a niacin pro-drug can favorably alter lipid profiles in animal models in animal models. Designing a niacin prodrug with the appropriate physical and chemical properties will allow control of the flux rate through the various layers of skin for the optimum sustained transdermal delivery of niacin. We propose to synthesize and evaluate prodrugs of niacins with formulation properties that will allow sustained delivery of niacin following topical application. We also will compare the effects of oral and transdermal administration of their ability to favorably alter lipid profiles in a double transgenic mouse model that contains lipoprotein profiles similar to the human.